TWI374134B - New process for the synthesis of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents
New process for the synthesis of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid Download PDFInfo
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Description
1374134 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種合成結構式（I) 7,8-二曱氧基-1，3-二 氫-2H-3-苯并氮呼-2-酮之方法，及其於合成依伐布雷定 (IVABRADINE)、其與醫藥上可接受酸之加成鹽及其水合 物之用途。1374134 6. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a synthetic structural formula (I) 7,8-dimethoxy-1,3-dihydro-2H-3-benzoazepine-2 a method of ketone, and its use in the synthesis of ivabradine (IVABRADINE), its addition salts with pharmaceutically acceptable acids and hydrates thereof.
根據本發明之方法得到的結構式（I)化合物適用於合成結 構式（II)依伐布雷定或3-{3-[{[(7S)-3,4-二曱氧基二環 [4.2.0]辛-1,3,5-三烯-7-基]甲基}(甲基）胺基]-丙基}-7,8-二 甲氧基-1，3,4,5-四氫-2H-3-苯并氮呼-2·酮、其與醫藥上可 接受酸之加成鹽及其水合物。The compound of formula (I) obtained according to the process of the invention is suitable for the synthesis of structural formula (II) ivabradine or 3-{3-[{[(7S)-3,4-didecyloxybicyclo[4.2] .0]octyl-1,3,5-trien-7-yl]methyl}(methyl)amino]-propyl}-7,8-dimethoxy-1,3,4,5- Tetrahydro-2H-3-benzoazepine-2·one, an addition salt thereof with a pharmaceutically acceptable acid, and a hydrate thereof.
(II)， 【先前技術】 依伐布雷定、及其與醫藥上可接受酸之加成鹽（尤指其 氫氯酸鹽）具有極珍貴的藥理及治療性質（尤其減慢心率性 質），使此等化合物適用於治療或預防心肌缺血之各種臨 床症狀，如：心絞痛症、心肌梗死及相關的心律不整，亦 用於多種病理，包括心律不整，尤其室上性心律不整，及 [ 140931.doc 1374134 用於心力衰蝎β 依伐布雷定及其與醫藥上可接受酸之加成鹽（尤指其氫 氯酸鹽）的製備與治療用途已在歐洲專利説明書ΕΡΟ 534 859中描述。 本發明描述自結構式（III)化合物形成依伐布雷定氫氣酸 鹽之合成：(II), [Prior Art] Evabradine, and its addition salts with pharmaceutically acceptable acids (especially its hydrochloride) have extremely valuable pharmacological and therapeutic properties (especially slowing heart rate properties), These compounds are suitable for the treatment or prevention of various clinical symptoms of myocardial ischemia, such as: angina pectoris, myocardial infarction and related arrhythmia, and are also used in a variety of pathologies, including arrhythmia, especially supraventricular arrhythmia, and [140931] .doc 1374134 Preparation and therapeutic use of heart failure beta ivabradine and its addition salts with pharmaceutically acceptable acids, especially its hydrochloride, are described in European Patent Specification 534 534 859 . The present invention describes the synthesis of a compound of formula (III) from the formation of ivabradine hydrogenate:
C1 (ΠΙ) 且參考用於製備此化合物之公開案J. Med. Chem 1990, 33(5)卷，1496-1504 。 該公開案所述用於結構式（III)化合物之合成路徑係利用 結構式（1)化*合物之烷化反應：C1 (ΠΙ) and refer to the publication for the preparation of this compound J. Med. Chem 1990, 33(5), 1496-1504. The synthetic route for the compound of formula (III) described in this publication utilizes the alkylation reaction of the formula (1):
(I). 上述公開案闡述結構式（I)化合物之製備，係利用作為中 間物且自（3,4-二甲氧基苯基）乙酸得到的Ν-(2,2·二甲氧基 乙基）-2-(3，4-二曱氧基苯基）乙醯胺。得到的苯乙醯胺在氫 氯酸的乙酸溶液存在下環化，生成結構式（I)化合物，相對 於（3，4-二甲氡基苯基）乙酸的總產量為5 8%。 鑒於依伐布雷定及其鹽對工業之價值，迫切需要尋找一 種有效的方法，尤其可得到極佳產量之結構式（1)7,8_二曱 氧基-1，3 -二鼠-2H-3 -笨并氮呼_2-嗣。 140931.doc 1374134 本申請者驚訝地發現藉由使用特定的操作條件，可在工 業規模上以大於92%之產量及大於99.5%之化學純度得到 結構式（I)化合物。 【發明内容】 本發明更具體地係關於一種合成結構式（I)化合物之方 法： CH，0 CH,0(I). The above publication describes the preparation of the compound of formula (I) by using ruthenium-(2,2.dimethoxyl) as an intermediate and obtained from (3,4-dimethoxyphenyl)acetic acid. Ethyl)-2-(3,4-dimethoxyoxyphenyl)acetamide. The obtained phenethylamine is cyclized in the presence of a hydrochloric acid solution of acetic acid to give a compound of the formula (I) in a total yield of 5 8% relative to (3,4-dimethylphenyl)acetic acid. In view of the industrial value of ivabradine and its salts, there is an urgent need to find an effective method, especially for the structural yield of (1) 7,8-didecyloxy-1,3-di--2H -3 - Stupid and nitrogen call_2-嗣. 140931.doc 1374134 The Applicant has surprisingly found that a compound of formula (I) can be obtained on an industrial scale with a yield of greater than 92% and a chemical purity of greater than 99.5% by using specific operating conditions. SUMMARY OF THE INVENTION The present invention more specifically relates to a method of synthesizing a compound of formula (I): CH, 0 CH, 0
(I)· 其特徵在於由結構式（IV)(3,4-二甲氧基苯基）乙酸 CH3〇V^ 〇I、1 义 （ιν) 轉化為結構式（V)化合物： CH3〇^\ 〇 R, (V). CH,0 其中基團心與!^可相同或不同，代表直鏈或具支鏈（Ci-Cd 烷氧基，或與攜載其的碳原子共同形成1,3-二氧己環、 1,3-二氧戊環或1,3-二氧庚環， 其在酸性介質中經環化反應，（分離後）得到結構式（I)化合 物。 【實施方式】 在本發明之較佳實施例中，結構式（IV)之化合物形成結 i s 1 140931.doc 13741,34 構式（v)化合物之轉化係在有機溶劑中，先轉化結構式（IV) 化合物形成结構式（VI)化合物： (VI)， CH3〇vt^1 0 其中’ X表示鹵素原子或者OCOR3基團，其中尺3為直鏈或 具支鏈（Ci-C6)烧基、苯基、苯甲基或咪嗤基團，及隨後由 結構式（VI)化合物與結構式（VII)化合物：(I)· is characterized by conversion of (3,4-dimethoxyphenyl)acetic acid CH3〇V^ 〇I, 1 (ιν) to a compound of formula (V): CH3〇^ \ 〇R, (V). CH,0 where the group heart and !^ may be the same or different, representing a straight chain or a branched chain (Ci-Cd alkoxy group, or together with the carbon atom carrying it, a 3-dioxane ring, a 1,3-dioxolane ring or a 1,3-dioxoheptane ring, which is subjected to a cyclization reaction in an acidic medium (after separation) to give a compound of the formula (I). In a preferred embodiment of the invention, the compound of formula (IV) forms a knot of is 1 140931.doc 13741,34. The conversion of the compound of formula (v) is carried out in an organic solvent, and the compound of formula (IV) is first converted. Forming a compound of formula (VI): (VI), CH3〇vt^1 0 wherein 'X represents a halogen atom or an OCOR3 group, wherein the rule 3 is a linear or branched (Ci-C6) alkyl group, a phenyl group, a benzyl or oxime group, and subsequently a compound of formula (VI) and a compound of formula (VII):
H2N^X(^R, 2 I (VII), R2 其中心與尺2基團可相同或不同’代表直鏈或具支鏈（Ci_C6) 烧氧基’或與攜載其的碳原子共同形成i，3_二氧己環' 1,3-二氧戊環或ι，3-二氧庚環， 在驗之存在下，於有機溶劑中進行縮合反應，得到結構式 (V)化合物：H2N^X(^R, 2 I (VII), R2 may be the same or different from the group of the ft 2, representing a straight or branched (Ci_C6) alkoxy group or formed together with the carbon atom carrying it i,3_dioxane' 1,3-dioxolane or ι,3-dioxoheptane, in the presence of a test, a condensation reaction in an organic solvent to give a compound of formula (V):
(V). 在本發明之另一較佳實施例中，結構式（IV)化合物形成 結構式（V)化合物之轉化係在耦聯劑之存在下，於有機溶 劑中’與結構式（VII)化合物反應： 14093l.doc(V). In another preferred embodiment of the present invention, the compound of the formula (IV) forms a conversion of the compound of the formula (V) in the presence of a coupling agent in an organic solvent and the structural formula (VII) Compound reaction: 14093l.doc
r2 (νπ)， 其中1^與112基團可相同或不同，其代表直鏈或具支鏈（c「 c6)烷氧基，或與攜載其的碳原子共同形成1，3-二氧己環、 1，3-二氧戊環或1，3-二氧庚環， 得到結構式（V)化合物：R2 (νπ), wherein the 1^ and 112 groups may be the same or different, and represent a straight or branched (c"c6) alkoxy group or together with the carbon atom carrying it to form 1,3-dioxo Cyclohexane, 1,3-dioxolane or 1,3-dioxoheptane gives the compound of formula (V):
用於結構式（VII)化合物與結構式（IV)化合物之縮合反應 之偶聯劑可提及（但未限制）以下試劑或試劑組：EDCI、 EDCI/HOBT 、 EDCI/HOAT 、 EDCI/NHS 、 DCC 、 DCC/HOBT、DCC/HOAT、DCC/NHS、HATU、HBTU、 TBTU、BOP、PyBOP、CDI、T3P。 在偶聯劑存在下，可用於結構式（VII)化合物與結構式 (IV)化合物之縮.合反應之有機溶劑可提及（但未限制）曱 苯、二氯甲烷、2-甲基四氫呋喃、氯苯、1,2-二氯乙烷、 氯仿及二氧己烷。 在本發明之一較佳實施例中，未分離結構式（V)化合 物。 在本發明之一較佳實施例中，未分離結構式（VI)化合 物。 結構式（VI)化合物中X基團較佳表示氯原子。 用於結構式（IV)化合物形成結構式（VI)化合物之轉化反 應的有機溶劑可提及（但未限制）曱苯、二氣甲烷、2-曱基 四氫呋喃、氣苯、1,2-二氣乙烷、氣仿與二氧己烷。 140931.doc 用於結構式（IV)化合物形成結構式（VI)化合物之轉化反 應的較佳有機溶劑為二氯曱烷。 結構式（IV)化合物形成結構式（VI)化合物之轉化反應的 溫度較佳為20至40°c。 用於結構式（IV)化合物形成結構式（VI)化合物（其中X表 示氣原子）之轉化反應的較佳試劑為亞硫醯氣。 用於結構式（IV)化合物形成結構式（VI)化合物之轉化反 應的亞硫醯氣用量較佳為1至1.3 mol/mol結構式（IV)化合 物。 用於結構式（VI)化合物與結構式（VII)化合物之反應的有 機溶劑可提及（但未限制）甲苯、二氯甲烷、2-曱基四氫呋 喃、氣苯、1，2-二氣乙烷、氣仿與二氧己烷。 用於結構式（VI)化合物與結構式（VII)化合物之反應的較 佳溶劑為二氣曱烷。 結構式（VI)化合物與結構式（VII)化合物之反應的溫度較 佳為0至40°c。 用於與結構式（VI)化合物之反應的結構式（VII)化合物用 量較佳為1至1.2 mol/mol結構式（VI)化合物。 用於結構式（VI)化合物與結構式（VII)化合物之反應的鹼 用量較佳為1至1.3 mol/mol結構式（VI)化合物。 可用於結構式（VI)化合物與結構式（VII)化合物之反應的 鹼可提及（但未限制）吡啶、DMAP與第三胺，例如三乙 胺、DIEA、N-甲基六氫吡啶、DBU、DABCO、DBN與N-曱基嗎啉。 140931.doc 1374134 用於結構式（VI)化合物與結構式（VII)化合物之反應的鹼 較佳為三乙胺。 可用於環化結構式（V)化合物以形成結構式（I)化合物之 酸可提及（但未限制）濃硫酸、多聚磷酸、濃氫氣酸的水溶 液、濃氫氯酸的醋酸溶液、濃氫溴酸的醋酸溶液及曱烷磺 酸。 用於環化結構式（V)化合物以形成結構式（I)化合物之反 應的酸用量較佳為5至15 mol/mol結構式（V)化合物。 在酸性介質中，結構式（V)化合物之環化反應溫度較佳 為0至40°C。 用於環化結構式（V)化合物以形成結構式（I)化合物之酸 較佳為濃硫酸。 當製程過程中未分離反應中間體時，結構式（V)化合物 的環化反應所用的濃硫酸用量較佳為1.5至3 ml/g結構式 (IV)(3,4-二甲氧基苯基）乙酸。 根據本發明方法得到的結構式（I)化合物尤其適用爲合成 依伐布雷定（IVABRADINE)、其與醫藥上可接受酸之加成 鹽及其水合物之合成中間體。 舉例來說，結構式（I)化合物與結構式（VIII)化合物之烷 基化反應 γ ^R4 (Vin)， r5 其中r4與r5可相同或不同，其分別代表直鏈或具支鏈（C^-c6)烷氧基，或與攜載其的碳原子共同形成1,3-二氧己環或 IS 1 140931.doc -10- 1374134 1，3-二氧戊環，Y代表鹵素原子，較佳為溴原子，或甲苯 確酸根、甲磺酸根或三氟甲磺酸根基團， 得到結構式（IX)化合物Coupling agents for the condensation reaction of a compound of formula (VII) with a compound of formula (IV) may include, but are not limited to, the following reagents or reagent sets: EDCI, EDCI/HOBT, EDCI/HOAT, EDCI/NHS, DCC, DCC/HOBT, DCC/HOAT, DCC/NHS, HATU, HBTU, TBTU, BOP, PyBOP, CDI, T3P. In the presence of a coupling agent, an organic solvent which can be used for the condensation reaction of the compound of the formula (VII) with the compound of the formula (IV) can be mentioned (but not limited to) toluene, dichloromethane, 2-methyltetrahydrofuran. , chlorobenzene, 1,2-dichloroethane, chloroform and dioxane. In a preferred embodiment of the invention, the compound of formula (V) is not separated. In a preferred embodiment of the invention, the compound of formula (VI) is not isolated. The X group in the compound of the formula (VI) preferably represents a chlorine atom. The organic solvent used for the conversion reaction of the compound of the formula (IV) to form the compound of the formula (VI) may be mentioned (but not limited to) toluene, di-methane, 2-mercaptotetrahydrofuran, benzene, 1,2-di Ethylene gas, gas and dioxane. 140931.doc A preferred organic solvent for the conversion of a compound of formula (IV) to form a compound of formula (VI) is dichlorodecane. The temperature at which the compound of the formula (IV) forms a conversion reaction of the compound of the formula (VI) is preferably from 20 to 40 ° C. A preferred reagent for the conversion reaction of a compound of formula (IV) to form a compound of formula (VI) wherein X represents a gas atom is sulphur sulfoxide. The sulfite gas used for the conversion reaction of the compound of the formula (IV) to form the compound of the formula (VI) is preferably used in an amount of from 1 to 1.3 mol/mol of the compound of the formula (IV). The organic solvent used for the reaction of the compound of the formula (VI) with the compound of the formula (VII) may be mentioned (but not limited to) toluene, dichloromethane, 2-mercaptotetrahydrofuran, gas benzene, 1,2-diqi B. Alkane, gas and dioxane. A preferred solvent for the reaction of the compound of formula (VI) with the compound of formula (VII) is dioxane. The temperature at which the compound of the formula (VI) is reacted with the compound of the formula (VII) is preferably from 0 to 40 ° C. The compound of the formula (VII) used for the reaction with the compound of the formula (VI) is preferably used in an amount of from 1 to 1.2 mol/mol of the compound of the formula (VI). The base used for the reaction of the compound of the formula (VI) with the compound of the formula (VII) is preferably used in an amount of from 1 to 1.3 mol/mol of the compound of the formula (VI). Bases which can be used in the reaction of a compound of formula (VI) with a compound of formula (VII) may mention, but are not limited to, pyridine, DMAP and a third amine such as triethylamine, DIEA, N-methylhexahydropyridine, DBU, DABCO, DBN and N-mercaptomorpholine. 140931.doc 1374134 The base used for the reaction of the compound of the formula (VI) with the compound of the formula (VII) is preferably triethylamine. Acids which can be used to cyclize the compound of formula (V) to form a compound of formula (I) may be mentioned (but not limited to) concentrated sulfuric acid, polyphosphoric acid, aqueous solution of concentrated hydrogen acid, acetic acid solution of concentrated hydrochloric acid, concentrated Acetic acid solution of hydrobromic acid and decanesulfonic acid. The acid used to cyclize the compound of the formula (V) to form the compound of the formula (I) is preferably used in an amount of from 5 to 15 mol/mol of the compound of the formula (V). In the acidic medium, the cyclization temperature of the compound of the formula (V) is preferably from 0 to 40 °C. The acid used to cyclize the compound of formula (V) to form a compound of formula (I) is preferably concentrated sulfuric acid. When the reaction intermediate is not separated during the process, the amount of concentrated sulfuric acid used in the cyclization reaction of the compound of the formula (V) is preferably from 1.5 to 3 ml/g of the structural formula (IV) (3,4-dimethoxybenzene). Base) acetic acid. The compounds of the formula (I) obtained according to the process of the invention are especially useful as synthetic intermediates for the synthesis of ivabradine, its addition salts with pharmaceutically acceptable acids and hydrates thereof. For example, the alkylation reaction of a compound of formula (I) with a compound of formula (VIII) γ ^R4 (Vin), r5 wherein r4 and r5 may be the same or different, each representing a straight chain or a branched chain (C ^-c6) alkoxy group, or together with the carbon atom carrying it, forms 1,3-dioxane or IS 1 140931.doc -10- 1374134 1,3-dioxolane, Y represents a halogen atom, Preferred is a bromine atom, or a toluene, mesylate or triflate group to give a compound of formula (IX)
其、纟it催化鼠化反應’得到相應的氫化之結構式（X)化合 物，And 纟it catalyzes the murine reaction to obtain the corresponding hydrogenated structural formula (X) compound,
(X)， 其中R4與K·5如結構式（VIII)定義， 脫除其二縮醛部分基團之保護基，得到結構式（XI)醛，(X), wherein R4 and K·5 are as defined in the formula (VIII), and the protecting group of the diacetal moiety is removed to obtain the aldehyde of the formula (XI).
其與（7S)-3,4-二甲氧基二環[4.2.0]辛·1，3,5-三烯-7-基]-N-曱基·曱胺在還原胺化反應條件下反應，得到依伐布雷 疋’其可視需要與選自下列之醫藥上可接受之酸轉化為其 加成鹽：氫氣酸、氫溴酸、硫酸、磷酸、醋酸、三氟乙 酸、礼酸、丙酮酸、丙二酸、琥珀酸、戍二酸、富馬酸、 酒石酸、馬來酸、檸檬酸、抗壞血酸、草酸、曱烷磺酸、 苯磺酸及樟腦酸，及轉化成其水合物。 140931.doc 1374134 所用縮寫： BOP:苯并三唑-1-基-氧-參（二曱基胺基）鱗六氟磷酸鹽 CDI:羰基二咪唑 DABCO:1,4-二氮雜二環[2.2.2]辛烷 〇丑1^:1，5-二氮雜二環[4.3.0]-壬-5-烯 〇811:1，8-二氮雜二環[5.4.0]十一-7-烯 DCC:二環己基碳化二亞胺 DIEA:N，N-二異丙基乙胺 DMAP:4-二甲胺基吡咬 EDCI: 1-(3-二甲基胺基丙基）-3-乙基-碳化二亞胺氫氣酸鹽 HATU:0-(7-氮雜苯并三唑-1-基）-1,1,3,3-四曱基脲鑌六 氟磷酸鹽 HBTU:0-(苯并三唑-1-基）-1,1,3,3-四曱基脲鑌六氟磷酸鹽 HOAT:N-羥基-7-氮雜苯并三唑 H0BT:1-羥基苯并三唑 NHS: N-羥基琥珀醯亞胺 NMP:N-曱基吡咯烷酮Reductive amination reaction conditions with (7S)-3,4-dimethoxybicyclo[4.2.0] osin-1,3,5-trien-7-yl]-N-indolyl decylamine The reaction is carried out to obtain ivabrabrate, which can be converted into a pharmaceutically acceptable acid selected from the group consisting of hydrogen acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, and acid. Pyruvic acid, malonic acid, succinic acid, azelaic acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, decanesulfonic acid, benzenesulfonic acid and camphoric acid, and converted into hydrates thereof. 140931.doc 1374134 Abbreviation used: BOP: benzotriazol-1-yl-oxo-gin (didecylamino) hexafluorophosphate CDI: carbonyl diimidazole DABCO: 1,4-diazabicyclo[ 2.2.2] Octane 〇 ugly 1^: 1,5-diazabicyclo[4.3.0]-non-5-ene fluorene 811:1, 8-diazabicyclo[5.4.0] eleven -7-ene DCC: dicyclohexylcarbodiimide DIEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridyl EDCI: 1-(3-dimethylaminopropyl) 3-ethyl-carbodiimide hydrogenate HATU: 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetradecylurea hexafluorophosphate HBTU :0-(benzotriazol-1-yl)-1,1,3,3-tetradecylurea hexafluorophosphate HOAT: N-hydroxy-7-azabenzotriazole H0BT: 1-hydroxyl Benzotriazole NHS: N-hydroxysuccinimide NMP: N-decylpyrrolidone
PyB0P:0-(苯并三唑-1-基）-氧基三吡咯烷基鱗六氟磷酸鹽 TBTU:0-(苯并三唑-1-基）-1,1,3,3-四曱基脲鑌六氟磷酸鹽 T3P:正丙基膦酸酐 以下實例闡述本發明。 7,8-二甲氧基-1,3-二氫-2H-3-苯并氮呼-2-酮之製備 #锣4 .· (3,4-二甲氧基苯基）乙酸氯化物 將135 g(3,4-二曱氧基苯基）乙酸與27〇 ml二氯曱烷注入 IS 1 140931.doc •12- 反應器中，然後使反應混合物之溫度升高至回流，且逐滴 加入90 g亞硫醯氣。在回流下攪拌該混合物3小時。所得 溶液即用於下一步驟。 步祕N-(2,2-二甲氧基乙基）_2·(34-二甲氧基苯基）乙酿胺 將225 ml二氣甲烷、44.15 §2,2_二甲氧基乙胺與44 35 § 一乙胺注入反應盗中，然後冷卻該混合物至丨〇。〇且逐滴加 入237.4 g上一步所得的溶液（相當於75 g(3,‘二甲氧基苯 基）乙酸），同時保持質量溫度在1〇〇c。在15〇c時攪拌該混 合物2小時。所得溶液即用於下一步驟。 步雜C. 7,8 -曱氧基-1，3-二氫- 2H-3 -苯并氮呼-2-酮 將150 ml 36 N硫酸加入包含上一步所得溶液且降至 i〇°c的反應器中’同時保持溫度在20°c以下。在i5_2〇t>c 下攪拌該混合物10小時，然後使反應混合物分離，且收集 包含產物的硫酸相。 自水/NMP混合物（4/1)沉澱、過濾及乾燥得到產物，其 相對於（3,4 -一曱氧基笨基）乙酸之產量為92.9%且化學純度 大於99.5 %。 140931.doc 13·PyB0P: 0-(benzotriazol-1-yl)-oxytripyrrolidinium hexafluorophosphate TBTU: 0-(benzotriazol-1-yl)-1,1,3,3-tetra Mercaptourea hexafluorophosphate T3P: n-propylphosphonic anhydride The following examples illustrate the invention. Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzoazepin-2-one #锣4··(3,4-dimethoxyphenyl)acetic acid chloride 135 g of (3,4-dimethoxyoxyphenyl)acetic acid and 27 〇ml of dichloromethane were injected into the IS 1 140931.doc •12-reactor, and then the temperature of the reaction mixture was raised to reflux, and 90 g of sulfoxide was added dropwise. The mixture was stirred under reflux for 3 hours. The resulting solution was used in the next step. Step by step N-(2,2-dimethoxyethyl)_2·(34-dimethoxyphenyl)ethylamine 225 ml of di-methane, 44.15 §2,2-dimethoxyethylamine Inject the reaction with 44 35 § monoethylamine, then cool the mixture to hydrazine. Then, 237.4 g of the solution obtained in the previous step (corresponding to 75 g (3, 'dimethoxyphenyl) acetic acid) was added dropwise while maintaining the mass temperature at 1 〇〇c. The mixture was stirred at 15 ° C for 2 hours. The resulting solution was used in the next step. Step C. 7,8-decyloxy-1,3-dihydro-2H-3-benzoazepin-2-one 150 ml of 36 N sulfuric acid was added to the solution containing the previous step and lowered to i〇°c In the reactor 'while keep the temperature below 20 ° c. The mixture was stirred at i5 2 〇t > c for 10 hours, then the reaction mixture was separated, and the sulfuric acid phase containing the product was collected. Precipitation from the water/NMP mixture (4/1), filtration and drying gave the product with a yield of 92.9% and a chemical purity of greater than 99.5% with respect to (3,4-dioxyphenyl)acetic acid. 140931.doc 13·
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| CN101774969B (en) * | 2009-01-13 | 2012-07-04 | 江苏恒瑞医药股份有限公司 | Ivabradine sulfate and method for preparing type I crystal thereof |
| EP2534135A2 (en) | 2010-02-12 | 2012-12-19 | KRKA, D.D., Novo Mesto | Novel forms of ivabradine hydrochloride |
| FR2956401B1 (en) | 2010-02-17 | 2012-02-03 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
| WO2011104723A2 (en) * | 2010-02-23 | 2011-09-01 | Ind-Swift Laboratories Limited | Acid addition salts of ivabradine and preparation thereof |
| HUP1000245A2 (en) * | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
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| HU230826B1 (en) * | 2014-11-19 | 2018-07-30 | Richter Gedeon Nyrt. | Process for preparation of benzazepine derivatives |
| EP3101010A1 (en) | 2015-06-03 | 2016-12-07 | Urquima S.A. | New method for the preparation of highly pure ivabradine base and salts thereof |
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